DESCRIPTION: (Applicant's abstract) TGF-beta may potentially be successful in the treatment of epithelial cancers since it inhibits the proliferation of responsive carcinoma cells and elicits differentiation- like effects. However, many poorly differentiated or highly aggressive carcinoma cells (i.e. colon, breast) have lost responsiveness to the growth inhibitory effects of TGF-beta. Alterations in TGF-beta signaling components likely represent major mechanisms underlying defects in TGF- beta responsiveness, yet little is known regarding TGF-beta signaling pathways, even in untransformed epithelial cells. During the previous award period, the applicant cloned the rat homologue (termed RSmad1) of MAD and has begun the functional analysis of this member of the Smad superfamily of novel signaling components. In addition, phosphorylated cytoplasmic regions of the TGF-beta receptors (CORT strategy) have been used to clone additional novel TGF-beta signaling components. During the next project period, guides will focus on determining the functional role of the novel component(s) cloned by the CORT strategy in the signaling of TGF-beta responses. Efforts with regard to the Smads will focus on defining both the significance of the Smad1 signaling protein in mediating specific TGF-beta responses, and the cross-talk between the Smads, the Ras/MAPK and related pathways, and the novel signaling pathways. The results obtained from this application will identify targets for the development of therapeutics that will either mimic the inhibitory effects of TGF-beta in epithelial cells or that will eliminate the development of resistance to growth regulation by TGF- beta.